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Rafiqul Gani - One of the best experts on this subject based on the ideXlab platform.
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a computer aided molecular design framework for Crystallization Solvent design
Chemical Engineering Science, 2006Co-Authors: Arunprakash T. Karunanithi, Luke E. K. Achenie, Rafiqul GaniAbstract:One of the key decisions in designing solution Crystallization processes is the selection of Solvents. In this paper, we present a computer-aided molecular design (CAMD) framework for the design and selection of Solvents and/or anti-Solvents for solution Crystallization. The CAMD problem is formulated as a mixed integer nonlinear programming (MINLP) model. Although, the model allows any combination of performance objectives and property constraints, in the case studies, potential recovery was considered as the performance objective. The latter, needs to be maximized, while other Solvent property requirements such as solubility, crystal morphology, flashpoint, toxicity, viscosity, normal boiling and melting point are posed as constraints. All the properties are estimated using group contribution methods. The MINLP model is then solved using a decomposition approach to obtain optimal Solvent molecules. Solvent design and selection for two types of solution Crystallization processes namely cooling Crystallization and drowning out Crystallization are presented. In the first case study, the design of single compound Solvent for Crystallization of ibuprofen, which is an important pharmaceutical compound, is addressed. One of the important issues namely, the effect of Solvent on the shape of ibuprofen crystals is also considered in the MINLP model. The second case study is a mixture design problem where an optimal Solvent/anti-Solvent mixture is designed for Crystallization of ibuprofen by the drowning out technique. for both case studies the performance of the Solvents are verified qualitatively through SLE diagrams.
Takuji Ogawa - One of the best experts on this subject based on the ideXlab platform.
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systematic structural elucidation for the protonated form of rare earth bis porphyrinato double decker complexes direct structural evidence of the location of the attached proton
Inorganic Chemistry, 2016Co-Authors: Kenichi Yamashita, Naoya Sakata, Takuji OgawaAbstract:Direct structural evidence of the presence and location of the attached proton in the protonated form of rare earth bis(porphyrinato) double-decker complexes is obtained from an X-ray diffraction study of single crystals for a series of protonated forms of bis(tetraphenylporphyrinato) complexes [MIII(tpp)(tppH)] (M = Tb, Y, Sm, Nd, and La). When CHCl3 is used as a Solvent for Crystallization of the complexes, their nondisordered molecular structures are obtained and the attached proton is identified on one of the eight nitrogen atoms. Use of other Solvents affords another type of crystal, in which the position of the proton is disordered and thus the molecular structure is averaged. La complex also affords the disordered average structure even when CHCl3 is used for Crystallization. A variable-temperature diffraction study for the Tb complex reveals that the dynamics of the proton in the nondisordered crystal is restricted.
Keshavarz Leila - One of the best experts on this subject based on the ideXlab platform.
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Influence of impurities on the solubility, nucleation, Crystallization and compressibility of paracetamol
'American Chemical Society (ACS)', 2020Co-Authors: Keshavarz Leila, Steendam, René R.e., Blijlevens, Melian A.r., Pishnamazi Mahboubeh, Frawley, Patrick J.Abstract:peer-reviewedThe striking ability of impurities to significantly influence Crystallization processes is a topic of paramount interest in the pharmaceutical industry. Despite being present in small quantities, impurities tend to considerably change a Crystallization process as well as the final crystalline product. In the present work, the effect of two markedly different impurities 4-nitrophenol and 4′-chloroacetanilide on the solubility, nucleation, and Crystallization of paracetamol is described. In the first part of this work, the fundamentals are outlined and show that, although each impurity led to a small increase in solubility of paracetamol, their effect as a nucleation inhibitor was much more pronounced. Induction time experiments were used in conjunction with the classical nucleation theory to show that the impurities did not affect the solid−liquid interfacial energy but instead significantly reduced the kinetic factor, overall resulting in reduced nucleation rates. Intriguingly, both impurities influenced the solubility and nucleation of paracetamol in a similar fashion despite their significant differences in terms of molecular structure, solubility, and ability to incorporate into the crystal structure of paracetamol. In the second part of this work, the incorporation of 4′-chloroacetanilide into the solid phase of paracetamol was investigated. The presence of 4′-chloroacetanilide in the solid phase of paracetamol significantly increased the compressibility of paracetamol, resulting in improved processability properties of paracetamol. The compressibility efficiency of paracetamol could be controlled using the amount of incorporated 4′-chloroacetanilide. Therefore, an experimental design space was developed and utilized to select the most important process parameters for impurity incorporation. Intriguingly, the number of carbon atoms in the aliphatic chain of the alcohol Solvent strongly correlated to the impurity incorporation efficiency. As a result, it was feasible to accurately control the compressibility and the amount of 4′-chloroacetanilide in the solid phase of paracetamol by simply choosing the required alcohol as the Solvent for Crystallization. Thus, the present work comprehensively shows how different impurities impact the key Crystallization mechanisms and properties of a pharmaceutical product. Rational process control over the incorporation of impurities and additives allows for advanced manufacturing of products with tailored specifications
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The importance of impurity on pharmaceutical processes
University of Limerick, 2019Co-Authors: Keshavarz LeilaAbstract:Solution Crystallization processes are widely treated as binary systems consisting of a solute and a Solvent. for real systems, additional components such as additives and impurities may significantly impact Crystallization processes even when present in very small amounts. An understanding of the mechanistic role of additives and impurities is therefore essential to design and control Crystallization processes. This thesis first describes the solubility and Crystallization of pure active pharmaceutical ingredients (API’s) from solution. Subsequently, it discusses the thermodynamic, kinetic and Crystallization effects, caused by impurities. Eventually, these knowledge were applied to optimize impurity removal processes by using a combined experimental-modelling approach to investigate a mother-liquor recycle operation and improve properties on the processability of API. The gravimetric solubility method and how solubility models cope with industrially-relevant complex products belonging to the α-Thio-β-chloroacrylamide family which is a class of highly versatile synthetic intermediates was examined. One of the drawbacks of the gravimetric method is the evaporation of Solvents which is due to elevated operating temperature or the volatile nature of the Solvent itself. Solubility data at higher temperatures, beyond the atmospheric boiling point of Solvents, allows for an increase in Crystallization yield. A pressurized-synthetic methodology was presented as a new technique for determining high-temperature solubility data even beyond the atmospheric boiling point. With the gravimetric method in combination with HPLC analysis, the effect of impurities (4-nitrophenol and 4’-chloroacetanilide) on the solubility of paracetamol has been determined and modelled. To study the effect of volume on the nucleation kinetics of paracetamol, an automated FBRM-method was applied to record induction times. The shear rate was rationalized to be the part of the kinetic parameter that changes most significantly when changing the crystallizer type, up to a specific volume beyond which the effect becomes negligible. Induction time experiments were used in combination with the classical nucleation theory and demonstrated that the impurities employed reduced the nucleation rate. The impurities did not affect the solid−liquid interfacial energy but significantly reduced the kinetic factor. The poor compression ability of paracetamol is well known. The crystal habit of paracetamol was altered in the present of structurally similar impurity (4’-chloroacetanilide) to improve the compaction behaviour of the paracetamol crystals. An experimental design space was developed and utilized to select the most important process parameters for impurity incorporation. As a result, it was feasible to accurately control the compressibility and the amount of 4’-chloroacetanilide in the solid phase of paracetamol by simply choosing the required alcohol as the Solvent for Crystallization. In Crystallization process, recycle of mother liquor allows for reduced waste and increased yield with complete control of the impurity concentration. A sequence of batch-cooling Crystallization experiments was demonstrated to investigate how a mother liquor recycle operation affects the Crystallization of paracetamol as a result of the gradual build-up of the impurity 4-nitrophenol. The results can be used as a guide to estimate the optimum mother liquor recycle conditions that would lead to reduced product and Solvent waste and improved process efficiency. The result of this thesis addresses a number of challenges in the Crystallization of API’s and impurities and leads to improved impurity removal processes. To obtain high yield as well as specific crystal quality attributes while maintaining a control on impurities, techniques strategies including continuous Crystallization with recycle and pressurized methods were developed. Furthermore, rational process control over the incorporation of impurities and additives allows for advanced manufacturing of products with tailored specifications
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Influence of impurities on the solubility, nucleation, Crystallization and compressibility of paracetamol
American Chemical Society, 2019Co-Authors: Keshavarz Leila, Steendam, René R.e., Blijlevens, Melian A.r., Pishnamazi Mahboubeh, Frawley, Patrick J.Abstract:The full text of this article will not be available in ULIR until the embargo expires on the 22/05/2020The striking ability of impurities to significantly influence Crystallization processes is a topic of paramount interest in the pharmaceutical industry. Despite being present in small quantities, impurities tend to considerably change a Crystallization process as well as the final crystalline product. In the present work, the effect of two markedly different impurities 4-nitrophenol and 4′-chloroacetanilide on the solubility, nucleation, and Crystallization of paracetamol is described. In the first part of this work, the fundamentals are outlined and show that, although each impurity led to a small increase in solubility of paracetamol, their effect as a nucleation inhibitor was much more pronounced. Induction time experiments were used in conjunction with the classical nucleation theory to show that the impurities did not affect the solid−liquid interfacial energy but instead significantly reduced the kinetic factor, overall resulting in reduced nucleation rates. Intriguingly, both impurities influenced the solubility and nucleation of paracetamol in a similar fashion despite their significant differences in terms of molecular structure, solubility, and ability to incorporate into the crystal structure of paracetamol. In the second part of this work, the incorporation of 4′-chloroacetanilide into the solid phase of paracetamol was investigated. The presence of 4′-chloroacetanilide in the solid phase of paracetamol significantly increased the compressibility of paracetamol, resulting in improved processability properties of paracetamol. The compressibility efficiency of paracetamol could be controlled using the amount of incorporated 4′-chloroacetanilide. Therefore, an experimental design space was developed and utilized to select the most important process parameters for impurity incorporation. Intriguingly, the number of carbon atoms in the aliphatic chain of the alcohol Solvent strongly correlated to the impurity incorporation efficiency. As a result, it was feasible to accurately control the compressibility and the amount of 4′-chloroacetanilide in the solid phase of paracetamol by simply choosing the required alcohol as the Solvent for Crystallization. Thus, the present work comprehensively shows how different impurities impact the key Crystallization mechanisms and properties of a pharmaceutical product. Rational process control over the incorporation of impurities and additives allows for advanced manufacturing of products with tailored specifications
Frawley, Patrick J. - One of the best experts on this subject based on the ideXlab platform.
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Influence of impurities on the solubility, nucleation, Crystallization and compressibility of paracetamol
'American Chemical Society (ACS)', 2020Co-Authors: Keshavarz Leila, Steendam, René R.e., Blijlevens, Melian A.r., Pishnamazi Mahboubeh, Frawley, Patrick J.Abstract:peer-reviewedThe striking ability of impurities to significantly influence Crystallization processes is a topic of paramount interest in the pharmaceutical industry. Despite being present in small quantities, impurities tend to considerably change a Crystallization process as well as the final crystalline product. In the present work, the effect of two markedly different impurities 4-nitrophenol and 4′-chloroacetanilide on the solubility, nucleation, and Crystallization of paracetamol is described. In the first part of this work, the fundamentals are outlined and show that, although each impurity led to a small increase in solubility of paracetamol, their effect as a nucleation inhibitor was much more pronounced. Induction time experiments were used in conjunction with the classical nucleation theory to show that the impurities did not affect the solid−liquid interfacial energy but instead significantly reduced the kinetic factor, overall resulting in reduced nucleation rates. Intriguingly, both impurities influenced the solubility and nucleation of paracetamol in a similar fashion despite their significant differences in terms of molecular structure, solubility, and ability to incorporate into the crystal structure of paracetamol. In the second part of this work, the incorporation of 4′-chloroacetanilide into the solid phase of paracetamol was investigated. The presence of 4′-chloroacetanilide in the solid phase of paracetamol significantly increased the compressibility of paracetamol, resulting in improved processability properties of paracetamol. The compressibility efficiency of paracetamol could be controlled using the amount of incorporated 4′-chloroacetanilide. Therefore, an experimental design space was developed and utilized to select the most important process parameters for impurity incorporation. Intriguingly, the number of carbon atoms in the aliphatic chain of the alcohol Solvent strongly correlated to the impurity incorporation efficiency. As a result, it was feasible to accurately control the compressibility and the amount of 4′-chloroacetanilide in the solid phase of paracetamol by simply choosing the required alcohol as the Solvent for Crystallization. Thus, the present work comprehensively shows how different impurities impact the key Crystallization mechanisms and properties of a pharmaceutical product. Rational process control over the incorporation of impurities and additives allows for advanced manufacturing of products with tailored specifications
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Influence of impurities on the solubility, nucleation, Crystallization and compressibility of paracetamol
American Chemical Society, 2019Co-Authors: Keshavarz Leila, Steendam, René R.e., Blijlevens, Melian A.r., Pishnamazi Mahboubeh, Frawley, Patrick J.Abstract:The full text of this article will not be available in ULIR until the embargo expires on the 22/05/2020The striking ability of impurities to significantly influence Crystallization processes is a topic of paramount interest in the pharmaceutical industry. Despite being present in small quantities, impurities tend to considerably change a Crystallization process as well as the final crystalline product. In the present work, the effect of two markedly different impurities 4-nitrophenol and 4′-chloroacetanilide on the solubility, nucleation, and Crystallization of paracetamol is described. In the first part of this work, the fundamentals are outlined and show that, although each impurity led to a small increase in solubility of paracetamol, their effect as a nucleation inhibitor was much more pronounced. Induction time experiments were used in conjunction with the classical nucleation theory to show that the impurities did not affect the solid−liquid interfacial energy but instead significantly reduced the kinetic factor, overall resulting in reduced nucleation rates. Intriguingly, both impurities influenced the solubility and nucleation of paracetamol in a similar fashion despite their significant differences in terms of molecular structure, solubility, and ability to incorporate into the crystal structure of paracetamol. In the second part of this work, the incorporation of 4′-chloroacetanilide into the solid phase of paracetamol was investigated. The presence of 4′-chloroacetanilide in the solid phase of paracetamol significantly increased the compressibility of paracetamol, resulting in improved processability properties of paracetamol. The compressibility efficiency of paracetamol could be controlled using the amount of incorporated 4′-chloroacetanilide. Therefore, an experimental design space was developed and utilized to select the most important process parameters for impurity incorporation. Intriguingly, the number of carbon atoms in the aliphatic chain of the alcohol Solvent strongly correlated to the impurity incorporation efficiency. As a result, it was feasible to accurately control the compressibility and the amount of 4′-chloroacetanilide in the solid phase of paracetamol by simply choosing the required alcohol as the Solvent for Crystallization. Thus, the present work comprehensively shows how different impurities impact the key Crystallization mechanisms and properties of a pharmaceutical product. Rational process control over the incorporation of impurities and additives allows for advanced manufacturing of products with tailored specifications
Arunprakash T. Karunanithi - One of the best experts on this subject based on the ideXlab platform.
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a computer aided molecular design framework for Crystallization Solvent design
Chemical Engineering Science, 2006Co-Authors: Arunprakash T. Karunanithi, Luke E. K. Achenie, Rafiqul GaniAbstract:One of the key decisions in designing solution Crystallization processes is the selection of Solvents. In this paper, we present a computer-aided molecular design (CAMD) framework for the design and selection of Solvents and/or anti-Solvents for solution Crystallization. The CAMD problem is formulated as a mixed integer nonlinear programming (MINLP) model. Although, the model allows any combination of performance objectives and property constraints, in the case studies, potential recovery was considered as the performance objective. The latter, needs to be maximized, while other Solvent property requirements such as solubility, crystal morphology, flashpoint, toxicity, viscosity, normal boiling and melting point are posed as constraints. All the properties are estimated using group contribution methods. The MINLP model is then solved using a decomposition approach to obtain optimal Solvent molecules. Solvent design and selection for two types of solution Crystallization processes namely cooling Crystallization and drowning out Crystallization are presented. In the first case study, the design of single compound Solvent for Crystallization of ibuprofen, which is an important pharmaceutical compound, is addressed. One of the important issues namely, the effect of Solvent on the shape of ibuprofen crystals is also considered in the MINLP model. The second case study is a mixture design problem where an optimal Solvent/anti-Solvent mixture is designed for Crystallization of ibuprofen by the drowning out technique. for both case studies the performance of the Solvents are verified qualitatively through SLE diagrams.